Person:

Hernan, Miguel

Background: The per-protocol effect is the effect that would have been observed in a randomized trial had everybody followed the protocol. Though obtaining a valid point estimate for the per-protocol effect requires assumptions that are unverifiable and often implausible, lower and upper bounds for the per-protocol effect may be estimated under more plausible assumptions. Strategies for obtaining bounds, known as “partial identification” methods, are especially promising in randomized trials. Results: We estimated bounds for the per-protocol effect of colorectal cancer screening in the Norwegian Colorectal Cancer Prevention trial, a randomized trial of one-time sigmoidoscopy screening in 98,792 men and women aged 50–64 years. The screening was not available to the control arm, while approximately two thirds of individuals in the treatment arm attended the screening. Study outcomes included colorectal cancer incidence and mortality over 10 years of follow-up. Without any assumptions, the data alone provide little information about the size of the effect. Under the assumption that randomization had no effect on the outcome except through screening, a point estimate for the risk under no screening and bounds for the risk under screening are achievable. Thus, the 10-year risk difference for colorectal cancer was estimated to be at least −0.6 % but less than 37.0 %. Bounds for the risk difference for colorectal cancer mortality (–0.2 to 37.4 %) and all-cause mortality (–5.1 to 32.6 %) had similar widths. These bounds appear helpful in quantifying the maximum possible effectiveness, but cannot rule out harm. By making further assumptions about the effect in the subpopulation who would not attend screening regardless of their randomization arm, narrower bounds can be achieved. Conclusions: Bounding the per-protocol effect under several sets of assumptions illuminates our reliance on unverifiable assumptions, highlights the range of effect sizes we are most confident in, and can sometimes demonstrate whether to expect certain subpopulations to receive more benefit or harm than others. Trial registration Clinicaltrials.gov identifier NCT00119912 (registered 6 July 2005) Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1056-8) contains supplementary material, which is available to authorized users.

Background: The survival difference between adherers and non-adherers to placebo in the Coronary Drug Project has been used to support the thesis that adherence adjustment in randomized trials is not generally possible and, therefore, that only intention-to-treat analyses should be trusted. We previously demonstrated that adherence adjustment can be validly conducted in the Coronary Drug Project using a simplistic approach. Here, we re-analyze the data using an approach that takes full advantage of recent methodological developments. Methods: We used inverse-probability weighted hazards models to estimate the 5-year survival and mortality risk when individuals in the placebo arm of the Coronary Drug Project adhere to at least 80% of the drug continuously or never during the 5-year follow-up period. Results: Adjustment for post-randomization covariates resulted in 5-year mortality risk difference estimates ranging from − 0.7 (95% confidence intervals (CI), − 12.2, 10.7) to 4.5 (95% CI, − 6.3, 15.3) percentage points. Conclusions: Our analysis confirms that appropriate adjustment for post-randomization predictors of adherence largely removes the association between adherence to placebo and mortality originally described in this trial. Trial registration ClinicalTrials.gov, Identifier: NCT00000482. Registered retrospectively on 27 October 1999. Electronic supplementary material The online version of this article (10.1186/s13063-018-2519-5) contains supplementary material, which is available to authorized users.

BACKGROUND: In many randomized controlled trials, patients and doctors are more interested in the per-protocol effect than in the intention-to-treat effect. However, valid estimation of the per-protocol effect generally requires adjustment for prognostic factors associated with adherence. These adherence adjustments have been strongly questioned in the clinical trials community, especially after 1980 when the Coronary Drug Project team found that adherers to placebo had lower 5-year mortality than non-adherers to placebo.

METHODS: We replicated the original Coronary Drug Project findings from 1980 and re-analyzed the Coronary Drug Project data using technical and conceptual developments that have become established since 1980. Specifically, we used logistic models for binary outcomes, decoupled the definition of adherence from loss to follow-up, and adjusted for pre-randomization covariates via standardization and for post-randomization covariates via inverse probability weighting.

RESULTS: The original Coronary Drug Project analysis reported a difference in 5-year mortality between adherers and non-adherers in the placebo arm of 9.4 percentage points. Using modern approaches, we found that this difference was reduced to 2.5 (95% confidence interval: -2.1 to 7.0).

CONCLUSION: Valid estimation of per-protocol effects may be possible in randomized clinical trials when analysts use appropriate methods to adjust for post-randomization variables.